2-imino-5-phenyl-4-oxazolidinone and a potentiating agent to treat parkinson{40 s disease

ABSTRACT

Covers the use of the combination of 2-imino-5-phenyl-4oxazolidinone or a salt thereof and a potentiating agent comprising an aluminum or alkaline earth metal salt or base in treating Parkinson&#39;&#39;s disease.

United States Patent Plotnikoff [451 Sept. 5, 1972 [54]2-IMINO-5-PHENYL-4- OXAZOLIDINONE AND A POTENTIATING AGENT TO TREATPARKINSON'S DISEASE [72] Inventor: Nicholas Peter Plotnikoff, LakeBluff, Ill.

[73] Assignee: Abbott Laboratories,

Chicago, Ill.

[52] US. Cl. ..424/157, 424/153, 424/154, 424/272 North [51] Int. Cl.A611: 27/00 [58] Field of Search ..424/272, 154, 157, 153

[56] References Cited UNITED STATES PATENTS 3,348,999 10/ 1967 Woroch..424/272 Primary Examiner-Stanley J. Friedman Att0rney-Robert L.Niblack [57] ABSTRACT Covers the use of the combination of2-imino-5-phenyl-4-oxazolidinone or a salt thereof and a potentiatingagent comprising an aluminum or alkaline earth metal salt or base intreating Parkinsons disease.

6 Claims, No Drawings Z-IMINO-5-PI-IENYL-4-OXAZOLIDINONE AND APOTENTIATING AGENT TO TREAT PARKINSON'S DISEASE CROSS REFERENCE TORELATED APPLICATIONS This application is a continuation-in-part ofcopending application U.S. Ser. No. 80,760, filed Oct. 14, 1970 nowabandoned.

BACKGROUND OF THE INVENTION Parkinsonism is generally characterized byinvoluntary tremors, diminished motor power and rigidity. The onset ofthe disease is insidious, with increasing rigidity or tremor or both.The patients facial expression may be fixed or less mobile than normal;smiling spreads and slowly disappears. Body movements generally becomeslower. There may be gradually increased rigidity with diminishedswaying of the arms during walking, Generally, the patients legs maybegin to feel stiff and excessive effort may be required to lift themfrom the ground while walking. Patients often assume a stooping postureand shuffle rather than walk. As the disease progresses, movements suchas adjusting a tie, buttoning a coat, etc. become impossible.

The disease is usually slowly progressive and patients may live for manyyears. However, with increased disability, patients often becomedepressed, anxious, and emotionally disturbed. While treatment withvarious drugs such as anti-spasmodics, central nervous system stimulantsand the like have been used alone or in combination to produce temporaryamelioration of complaints, l-dopa was the first effective single agentin the treatment of the disease.

L-dopa has been reported to be effective against the akinesia andrigidity of Parkinsonism, particularly in extremely severe cases. Anincrease in mental alertness and wakefulness, relief from depression andan increase in intellect has also been observed.

While l-dopa has produced some rather promising results in experimentaltherapy, unfortunately it is not well tolerated by a number of patients.The most frequent side effects are nausea, vomiting, hypotension, andabnormal involuntary movements, as well as mental changes. The abnormalinvoluntary movements particularly pose severe problems to its continueduse of approximately in 50 percent of its patients. Thus, it is evidentthat drugs having a minimum of unwanted complications are needed totreat patients suffering from Parkinsonism.

SUMMARY OF THE INVENTION It, therefore, becomes an object of theinvention to provide a method of treating Parkinsonism. A specificmethod of the invention is to provide a method of treating Parkinsonismwith a drug exhibiting a low level of side effects, if any, and whichdoes not become tolerated over extended usage. Essentially the inventionhere is concerned with a method of treating Parkinsons disease with acomposition comprising in combination 2-imino-5-phenyl-2-oxazolidinoneor a salt thereof and a potentiating agent comprising an aluminum oralkaline earth metal salt or base.

DETAILED DESCRIPTION OF THE INVENTION In more detail, compositions founduseful here in treating Parkinsonism comprise the combination of 2-imino-S-phenyl-4-oxazolidinone and a wide variety of aluminum oralkaline earth metal salts or bases. While the oxazolidinone compounditself is known to have some activity against Parkinsons disease it hasbeen discovered here that its activity in this area may be substantiallyincreased by combining said oxazolidinone with an aluminum or alkalineearth metal base or salt. Such potentiation of the effect of theoxazolidinone is accomplished by combination with a salt or base,despite the fact that the salt or base alone, even in rela tively largedosages is substantially ineffective in this treatment area.

Typical potentiating agents include aluminum, magnesium and calciumcarbonates, hydroxides, sulfates, chlorides, bicarbonates, phosphates,citrates, thiosulfates, iodides, bromides, carbonate-hydroxides,acetates, propionates, lactates, benzoates, tartrates, etc. Mostpreferred are magnesium salts and bases such as magnesium hydroxide,magnesium sulfate, magnesium chloride. One particularly usefulcomposition comprises a combination of percent by weight ofoxazolidinone and 25 percent by weight of magnesium hydroxide, whereinapproximately equimolar amounts of each are present.

In the typical situation the compositions employed here which exhibitanti-Parkinsonism activity are formed by combining one or more of thejust described salts or bases with the oxazolidinone in a ratio of atleast 0.05 mole of base or salt to 1 mole of oxazolidinone. While noupper limit of said ratio is to be construed, yet as a practical matter,up to about 50 or more moles of bases per mole of oxazolidinone may becombined to form useful treatment compositions.

For use in treating Parkinsons disease it may be administered in eitherliquid or solid form. Thus, the active compounds may be provided ingranulation, tablet, capsule, elixir and other dosage forms. Oraladministration is preferred and is the most convenient. Other means ofadministration may be employed such as, for example, by intraperitionealor intramuscular injection. The active ingredients can also beincorporated in an oil or wax base and administered in the form of asuppository.

The compounds of the invention are found to be effective in humans at adosage range of from about 0.1

to about 200 mg./kg. of body weight daily. More often the dose is 0.1-mg./kg. and most often is 1-100 mg./kg.

EXAMPLE I One basic approach for evaluation of anti-Parkinson activityis estimating reversal of the extrapyramidal effects of reserpine whichdepletes biogenic amines in animals and in man, which test was employedhere.

A composition comprising a mixture of 2-imino-5- phenyl-4-oxazolidinonewith magnesium hydroxide (75.3 percent and 24.7 percent by weight,respectively) was prepared in a liquid form and administered to mice.The composition was found to reverse the effects of deserpidine in micewith a dosage range of 25-100 mg./kg., i.p. In another series of testsinvolving six Rhesus monkeys the effects of deserpidine were reversed inan oral dose range of -20 mg./kg. orally.

EXAMPLE II The above composition was also studied for its anti-Parkinson activity in additional tests. Specifically, it was studiedwith respect to its activity in reversing the motor activity effects oftetrabenazine (a reserpine-like drug) in mice. As is shown below, thecomposition demonstrated marked activity in reversing the sedativeeffects of tetrabenazine, which depletes brain biogenic amines.

Here the composition was made up in the form of a capsule andadministered orally. The capsule mixture was composed as follows:

' Composition 1 Ingredients Grams 2-imine5-phenyl-4-oxazolidinone 3.76magnesium hydroxide 1.24 lactose l 5 .00

Total The activity of the above composition is as follows:

In analyzing data from the above the table, it should be noted that ineach instance the t test p value was significantly different from thecontrols.

It is understood, of course, that in addition to use of the above saltsor bases in combination with 2-irnino-5- phenyl-4-oxazolidinone itself,salts of the oxazolidinone compound may also be employed here. Thisparticular oxazolidinone is a relatively weak acid, and therefore saltsmay be formed via combination with a strong base. For example, alkalimetal salts may be formed such as the sodium, lithium, etc. salts. Inaddition alkaline earth metal salts such as the calcium salt may also beformed. Normally, these salts are formed by reacting the oxazolidinonewith a strong alkali metal or alkaline earth metal base-or anhydridesuch as sodium hydroxide, potassium hydroxide, lithium hydroxide,calcium hydroxide etc., or sodium hydride, calcium hydride.

What is claimed is: y

l. A method of treating a patient suffering from Parkinsons diseasecomprising the step of administering to said patient at least aneffective dosage of a composition comprising in combination Z-i rinO-S-phen l-4-oxazolldlnone or a pharmaceutic ly accepta le saltthereof and a potentiating agent comprising a base or salt selected fromthe group consisting of an aluminum base, an aluminum salt, an alkalineearth metal salt and an alkaline earth metal bases said potentiatingagent being combined in a ratio of at least 0.05 mole of potentiatingagent to 1 mole of 2-imino-5-phenyl-4-oxazolidinone.

2. The method of claim 1 wherein said potentiating agent is magnesiumhydroxide.

3. The method of claim 2 wherein said magnesium hydroxide is combined ina ratio of about 1 mole of magnesium hydroxide to 1 mole of2-imino-5-phenyl-4- oxazolidinone.

4. The method of claim 1 wherein said dosage range is from about O.l toabout 200 mg./kg. of body weight daily.

5. The method of claim 4 wherein said dosage range is 0. 1-100 mg./kg.

6. The method of claim 1 wherein said composition is administered in aunit dosage form in a pharmaceutically acceptable carrier, said carriercomprising a major portion of said dosage form.

2. The method of claim 1 wherein said potentiating agent is magnesiumhydroxide.
 3. The method of claim 2 wherein said magnesium hydroxide iscombined in a ratio of about 1 mole of magnesium hydroxide to 1 mole of2-imino-5-phenyl-4-oxazolidinone.
 4. The method of claim 1 wherein saiddosage range is from about 0.1 to about 200 mg./kg. of body weightdaily.
 5. The method of claim 4 wherein said dosage range is 0.1- 100mg./kg.
 6. The method of claim 1 wherein said composition isadministered in a unit dosage form in a pharmaceutically acceptablecarrier, said carrier comprising a major portion of said dosage form.